Preferential modulatory action of 5-HT2Areceptors on the dynamic regulation of basal ganglia circuits
J. Neurosci.. 2022-11-18; : JN-RM-1181-22
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Guilhemsang L(1)(2)(3), Gutierrez-Ceballos A(1), Antonazzo M(1)(4), Mallet N(2)(3), Ugedo L(1)(4), Morera-Herreras T(5)(4).
(1)Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), 48940-Leioa, Spain.
(2)Université de Bordeaux, Institut des Maladies Neurodégénératives, 33076 Bordeaux, France.
(3)CNRS UMR 5293, Institut des Maladies Neurodégénératives, 33076 Bordeaux, France.
(4)Neurodegenerative diseases Group, Biocruces Health Research Institute, Barakaldo, Bizkaia, Spain.
(5)Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), 48940-Leioa, Spain. .
In rodents, cortical information is transferred to the substantia nigra pars
reticulata (SNr) through motor and medial prefrontal (mPF) basal ganglia (BG)
circuits implicated in motor and cognitive/motivational behaviours,
respectively. The serotonergic 5-HT2A receptors are located in both of these
neuronal networks, displaying topographical differences with a high expression
in the associative/limbic territories, and a very low expression in the
subthalamic nucleus (STN).This study investigated if the stimulation of 5-HT2A
receptors could have a specific signature on the dynamic regulation of BG
circuits, preferentially modulating the mPF information processing through
trans-striatal pathways. We performed in vivo single-unit extracellular
recordings to assess the effect of the 5-HT2A agonist TCB-2 on the spontaneous
and cortically evoked activity of lateral and medial SNr neurons in male rats
(involved in motor and mPF circuits, respectively).TCB-2 (50-200 μg/kg, i.v.)
increased the basal firing rate and enhanced the cortically evoked inhibitory
response of medial SNr neurons (transmission through the direct striato-nigral
pathway). A prior administration of the preferential 5-HT2A receptor antagonist
MDL11939 (200 μg/kg, i.v.) did not modify any electrophysiological parameter,
but occluded TCB-2-induced effects. In animals treated with the 5-HT synthesis
inhibitor pCPA, TCB-2 failed to induce abovementioned effects, thus suggesting
the contribution of endogenous 5-HT. However, the mobilisation of 5-HT induced
by the acute administration of fluoxetine (10 mg/kg, i.p.), did not mimic the
effects triggered by TCB-2. Overall, these data suggest that 5-HT2A receptors
have a preferential modulatory action on the dynamic regulation of BG
circuitry.SIGNIFICANT STATEMENT:Motor and medial prefrontal (mPF) basal ganglia
(BG) circuits play an important role in integrative brain functions like
movement control or cognitive/motivational behaviour, respectively. Although
these neuronal networks express 5-HT2A receptors, the expression is higher in
associative/limbic structures than in the motor ones. We show a
topographical-dependent dissociation in the effects triggered by the 5HT2A
agonist TCB-2, which specifically increases the medial substantia nigra pars
reticulata (SNr) neuron activity and has a preferential action on mPF
information processing through the striato-nigral direct pathway. These are very
likely to be 5-HT2A receptor-mediated effects that require mobilisation of the
endogenous 5-HT system. These findings provide evidence about the specific
signature of 5-HT2A receptors on the dynamic regulation of BG circuits.
Copyright © 2022 the authors.
Conflict of interest statement: The authors declare no competing financial interests